Page 103 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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Treatment Group (N0044).
Am J Clin Oncol 2007;30:507- 13.
ref. 24 – FU, comb
Magné N et al. Dihydropyrim idine dehydrogenas e activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity.
Br J Clin Pharmacol 2007;64:237- 40.
ref. 25 - FU/CAP, mono
Saif MW et al. Dihydropyrim idine dehydrogenas e deficiency (GPD) in GI malignancies: experience of 4-years.
Pak J Med Sci Q 2007;23:832- 9.
Level of evidence score: 3
gene act. 1:CTC-AE 4(2)#
131 French patients with poor tolerance to FU combination or monotherapy (grade II neurotoxicity or grade III-IV toxicity), including 9 fatalities, and 185 unselected patients; screening for DPD activity in peripheral mononuclear blood cells and for *2A (IVS14+1G>A).
- 81% of the toxicity occurred during the 1st cycle of FU chemotherapy.
- Inverse association between DPD activity and toxicity score (sum of the different toxicity grades per patient) (S).
- Percentage of patients with clear or severe DPD deficiency was higher in the case group than in the control group (17% versus 2.7% and 6% versus 0% respectively).
- Inverse association between lethal toxicity and DPD activity (S).
- Inverse association between the severity of the individual types of toxicity (grade II central neurotoxicity; grade IV mucositis, diarrhoea, neutropenia or thrombocytopenia) and DPD activity (all five S). Median DPD activity was 1.6-3.2x lower in patients with severe toxicity.
- Only 2 in 93 screened cases (2.2%) had *2A (both *1/*2A). Both had low DPD activity and high toxicity scores during the 1st cycle. Neither died.
23 patients with excessive toxicity on FU (n=8) or capecitabine therapy (n=15), including 16 Caucasians, 3 Afro-Americans and 3 South-Asians; screening for DPD activity in peripheral mononuclear blood cells and by genotyping.
- 30% of the patients had DPD deficiency (n=7), including 3 who were treated with FU (500 mg/m2 per week or 425 mg/m2 per week) and folinic acid, 2 who were treated with capecitabine 1800 mg/m2 and 2 who were treated with high-dose bolus FU (1400 mg/m2) in combination with the uridine prodrug 2’,3’,5’-tri-O-acetyluridine. The deficiency was confirmed by genotyping in 1 patient: he was *1/*2A. - 28% of the DPD-deficient patients died due to toxicity (n=2), including 1 to capecitabine and 1 to high-dose bolus FU.
- Re-challenge with capecitabine of a patient treated with FU/ folinic acid led to grade III hand-foot syndrome.
Authors’ conclusion:
“Present data
suggest that IVS14+1 4 mutation screening
has limited
effectiveness in
identifying patients
at risk for severe 5FU
toxicity.”
Level of evidence score: 2
gene act. 1: CTC- AE 4
Authors’ conclusion: “Screening patients for DPD deficiency prior to administration of 5- FU or capecitabine using 2-13C uracil breath test could potentially lower risk of toxicity.”
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